The elastic fibers and the collagens are the major components of the lung connective tissue network. A complex process of structural remodeling of these components occurs in emphysema. MMPs comprise a family of proteolytic enzymes that are involved in remodeling of the extracellular matrix. To investigate the expression of MMPs and TIMPs in emphysema, we performed immunohistochemical staining (peroxidase) for MMP-1, MMP-2, MMP-9, TIMP-1, TIMP-2 and Type IV collagen on paraffin sections of lung from 4 normal control subjects and 22 patients with emphysema of various causes. In control lungs, endothelial cells, bronchiolar epithelial cells and smooth muscle cells showed very weak reactions for MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2; alveolar epithelial cells gave negative to weak reactions, and alveolar basement membranes were negative for MMPs and TIMPs. In most patients with emphysema, the endothelial cells showed stronger reactions for MMP-1, MMP-2, MMP-9 and TIMP-2. MMP-1 and MMP-2 also were focally localized in the basement membranes of endothelial and epithelial cells of the alveolar walls and around elastic fibers. In addition, TIMP-2 was observed in these regions. Compared to those in control lungs, alveolar macrophages also showed an increase reactivity for MMP-2 and MMP-9. These findings provide support for the novel concept that MMPs derived from pulmonary endothelial cells and macrophages play an important role in the connective tissue destruction that characterizes emphysema.